Tuberculosis is a persistent human pathogen that threatens the health of people throughout the world, especially in developing countries. Although tuberculosis is both a treatable and preventable condition, current public health strategies that focus on directly observed therapy have failed to control the disease in Sub-Saharan Africa where tuberculosis control is compounded by the HIV epidemic, the emergence of multi-drug resistant disease, and fragile infrastructure for public health. One reason for the limited success of this strategy is that it is a prescription of treatment of tuberculosis, it doesnot prevent subsequent cases among contacts of infectious cases. This proposal is designed around a new paradigm for tuberculosis control that is built upon a basic tenet in epidemic theory. That is, tuberculosis epidemics are perpetuated when one case is replaced by one or more cases among contacts. Unless subsequent cases are prevented, there will be little progress with tuberculosis control. Case studies, molecular epidemiology and community trials all point to transmission in the community as the driving force behind tuberculosis epidemics. The scientific goal of this project is to understand transmission of M. tuberculosis in an urban African setting. The extended, applied goal is to add cost-effective strategies aimed at interrupting transmission of M. tuberculosis to current global approaches to tuberculosis control. To address the Specific Aims of this proposal, we will conduct two inter-related epidemiologic studies in the Rubaga Division of Kampala Uganda. We will perform a cross-sectional study that compares the social networks, mixing patterns, microbial networks, individual risk characteristics, and geographic context between index tuberculosis cases and neighborhood matched controls. We will also perform a case- cohort study within a prospective cohort to determine the incidence of new tuberculosis infection and relate it to high risk environments, mixing patterns and geographic location of social networks. This application has been revised according to the recommendations of the study section and now includes the results of a pilot project. The results further support the basic premise of the study and show its feasibility. The proposed projects will integrate methods from diverse fields such as molecular epidemiology, social network analysis, and geographic information systems to open up a new way to approach tuberculosis control that will exert a sustained and powerful influence on the field. PUBLIC HEALTH RELEVANCE: This proposal addresses the globally important problem of tuberculosis. Through the study of social networks of tuberculosis cases, the project will seek to fill gaps in our knowledge about the spread of tuberculosis in African cities. By the conclusion of this project, we hope to have valid evidence on which to base new ways to control tuberculosis that mitigate or block transmission.